Discovery of an orally efficacious imidazo[5, 1-f]-[1,2,4]triazine dual inhibitor of IGF-1R and IR

Article abstract of DOI:10.1021/ml100178g

This report describes the investigation of a series of 5,7-disubstituted imidazo[5,1-f][1,2,4]triazine inhibitors of insulin-like growth factor-1 receptor (IGF-1R) and insulin receptor (IR). Structure-activity relationship exploration and optimization lea

Full text of DOI:10.1021/ml100178g

pubs.acs.org/acsmedchemlett
Discovery of an Orally Efficacious Imidazo[5,1-f]-
[1,2,4]triazine Dual Inhibitor of IGF-1R and IR
Meizhong Jin,*,† Prafulla C. Gokhale,‡ Andy Cooke,‡ Kenneth Foreman,† Elizabeth Buck,†
Earl W. May,† Lixin Feng,‡ Mark A. Bittner,‡ Mridula Kadalbajoo,† Darla Landfair,‡
Kam W. Siu,† Kathryn M. Stolz,† Douglas S. Werner,† Radoslaw S. Laufer,† An-Hu Li,†
Hanqing Dong,† Arno G. Steinig,† Andrew Kleinberg,† Yan Yao,† Jonathan A. Pachter,†
Robert Wild,‡ and Mark J. Mulvihill*,†
†OSI Oncology, OSI Pharmaceuticals, Inc., 1 Bioscience Park Drive, Farmingdale, New York 11735, and
‡OSI Oncology, OSI Pharmaceuticals, Inc., 2860 Wilderness Place, Boulder, Colorado 80301
ABSTRACT This report describes the investigation of a series of 5,7-disubstituted
imidazo[5,1-f ][1,2,4]triazine inhibitors of insulin-like growth factor-1 receptor
(IGF-1R) and insulin receptor (IR). Structure-activity relationship exploration and
optimization leading to the identification, characterization, and pharmacological
activity of compound 9b, a potent, selective, well-tolerated, and orally bioavailable
dual inhibitor of IGF-1R and IR with in vivo efficacy in tumor xenograft models, is
discussed.
KEYWORDS Insulin-like growth factor-1 receptor (IGF-1R), insulin receptor (IR),
inhibitors, structure-based drug design (SBDD), cancer
nsulin-like growth factor-1 receptor (IGF-1R) is a tetra-
meric transmembrane receptor tyrosine kinase activated
I
by the binding of its cognate ligands IGF-1 and IGF-2.1,2
Preclinical studies show that activation of IGF-1R is required for
cellular transformation and tumorigenesis, and inhibition of IGF-
1R activity results in reduced growth of tumor xenografts.3-8
The importance of IGF-1R as an anticancer target is further
underscored by its role in promoting resistance to cytotoxic
chemotherapies, as well as molecular targeted therapies includ-
ing HER2 and EGFR antagonists.3,9-13 Validation of IGF-1R as an
anticancer target has been demonstrated by several monoclonal
antibodies directed against the receptor's extracellular ligand
binding domain in the clinical setting.14 However, efficacy
mediated by IGF-1R-selective MAbs may be limited due to lack
of coverage on the structurally related insulin receptor (IR). A
growing body of data supports the importance of the IR in tumor
cell proliferation and survival. Increased expression of IR is
observed in several types of human cancers, and activation of
IR by either insulin or IGF-2 results in enhanced proliferation of
select human tumor cell lines.7,15-19 Moreover, bidirectional
cross-talk between IGF-1R and IR can occur whereby inhibition
of either receptor individually results in a compensatory increase
in the phosphorylation state of the reciprocal receptor. For
xenografts coexpressing IGF-1R and IR, dual inhibition of both
receptors results in greater antitumor activity as compared to
inhibiting IGF-1Ralone.20 These results have provided a rationale
for dual IGF-1R/IR inhibition as a treatment of cancer.
Figure 1. OSI-906.
in advanced clinical development (Figure 1).22,23 While the
main thrust of our IGF-1R/IR small molecule drug discovery
efforts focused primarily on the imidazopyrazine series, alter-
nate bioisosteric cores were also considered. Herein, we report
the discovery of imidazo[5,1-f][1,2,4]triazine-based inhibitors of
IGF-1R and IR and, particularly, compound 9b as a potent,
selective, orally bioavailable dual IGF-1R and IR inhibitor with in
vivo efficacy in mouse xenograft models.
As shown in Scheme 1, the initial proof-of-concept 5,7-
disubstituted imidazo[5,1-f][1,2,4]triazine compound 1a was
synthesized via a Suzuki coupling of intermediate 2 (X = N)24
with boronate 3a. Compound 1a showed activity against IGF-1R
both biochemically and cellularly (Table 1). However, a
Recently, small molecular kinase inhibitors targeting both
IGF-1R and IR have been developed and advanced into clinical
studies.21 We have previously disclosed our work around
imidazo[1,5-a]pyrazine derived small molecule dual IGF-1R/IR
inhibitors, including the discovery of OSI-906, which is currently
Received Date: July 23, 2010
Accepted Date: August 14, 2010
Published on Web Date: August 30, 2010
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Scheme 1. Synthesis of Imidazo[5,1-f][1,2,4]triazine IGF-1R Inhi-
bitor 1aa
aReagents and conditions: (a) PdCl2(dppf), K2CO3, dioxane-water
(4:1, v:v), 95 °C, 70-75%.
Figure 2. Modeled interaction of the quinoline moiety of 1a with
the catalytic lysine (K1003) of IGF-1R.25 The lysine nitrogen is
closer to the C8-H than to the N1. One proton points directly to the
C8-H position in the lowest energy rotamer of the amine
(depicted), while a nearly eclipsed conformation is required to
point a proton directly at the N1 position.
Table 1. In Vitro Potency and Microsomal Stability of Compounds
1a and 1b
IGF-1R
IGF-1R cell
extraction ratios
biochemicala mechanisticb
compound
X
IC50 (μM)
IC50 (μM)
mouse
human
preferred, as the fluorine serves as a hydrogen bond acceptor,
has small van der Waals volume, is metabolically inert, and
approaches closer to the basic amine on K1003 than the lone
pair on a ring nitrogen would.
1a
1b
N
0.27
0.33
0.89
0.88
0.91
0.85
CH
0.079
0.086
aA 100 μM concentration of ATP. b LISN cell line.
The synthetic chemistry used to prepare these advanced
imidazotriazine analogues is shown in Scheme 2. Amide 6
was prepared from coupling of 5-methoxy-[1,2,4]triazin-6-
ylmethylamine 424 with the activated cyclobutanone ester 5.
Subsequent POCl3 cyclization followed by bromination af-
forded common intermediate 7. The cyclobutanone moiety
of 7 was converted to a tertiary alcohol via a Grignard
reaction yielding the cis-isomer stereoselectively. Ammono-
lysis gave compound 8, and compound 9 was obtained after
a Suzuki coupling of 8 with boronate 3. Alternatively, 7 was
subjected to ammonolysis followed by reductive amination
to provided compound 10, which went on to a Suzuki
coupling with boronate 3 to give final compound 11.
As shown in Table 2, the addition of a fluorine atom at the
C8 position of the quinoline ring boosted potency, in accord
with the binding affinity hypothesis. These compounds
inhibited IR and IGF-1R with similar potencies and showed
improved in vitro microsomal stability when compared
to 1a.
On the basis of their in vitro profiles, compounds 9b, 11b,
and 11d were prioritized for mouse PK evaluation at 5 mg/kg
for iv dose and 25 mg/kg for oral dose. Key mouse PK para-
meters for these compounds are summarized in Table 3.
Compounds 11b and 11d showed lower exposure and bioavail-
ability as compared to 9b, presumably due to their lower
permeability as indicated by PAMPA data, especially at lower
pH. The apparent oral bioavailability in excess of 100% for 9b
may indicate saturation of a clearance mechanism. On the
basis of its overall in vitro and DMPK profile, 9b was selected for
further profiling.
significant loss in potency was observed as compared to its
counterpart 1b, an early lead compound from the imidazo-
[1,5-a]pyrazine series from which OSI-906 emerged.22 We
hypothesized that the decrease in potency derived from
weaker hinge hydrogen-bonding interactions due to a re-
duction in the electron richness of the donor and acceptor in
1a as compared to 1b. Differences in desolvation between
the two agents may also play a contributing role. In either
event, our efforts focused on increasing the potency through
further modifications to 1a.
To expedite the lead optimization process, we decided to
generate a focused library based on the structural insights
and structure-activity relationship (SAR) developed around
the earlier imidazo[1,5-a]pyrazine series.22,23 In that series, a
hydrogen bond between the quinoline nitrogen and the
basic amine of Lys1003, in addition to the hydrogen bonds
to the hinge, are critical for activity. Furthermore, the imida-
zopyrazine C3 substituent, which exited out to solvent,
allowed for the control of overall drug metabolism and
pharmacokinetic (DMPK) properties. Hence, in the imidazo-
triazine series, improving the quinoline's acceptor pharma-
cophore became the major focus for improving potency. The
C7 substituent was limited to three preferred substituted
cyclobutyl analogues, which showed favorable DMPK prop-
erties and maintained both IGF-1R and IR target potency
within the imidazopyrazine series. Detailed consideration of
the quinoline's interaction with Lys1003 led to the hypoth-
esis that a hydrogen bond acceptor at the C8 position of the
quinolinyl moiety could further strengthen this interaction
and thus enhance activity (Figure 2). The space adjacent to
the C8 position is sterically congested, limiting replacements
of the C8-H to either N8 or C8-F. Fluorine substitution is
The in vitro and in vivo drug discovery cascade focused
primarily on a GEO human colorectal tumor cell line. The
GEO cell line was chosen since it represents a naturally
occurring IGF-1R/IR/IGF2 autocrine loop driven tumor line
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Scheme 2. General Synthesis Schemea
aReagents and conditions: (a) 10% aqueous NaHCO3, THF, room temperature. (b) POCl3, DMF/MeCN, room temperature. (c) NBS, DMF. (d) MeMgCl,
THF, -78 °C. (e) 2 N NH3 in iPrOH, 50 °C. (f) PdCl2(dppf), K2CO3, dioxane-water (4:1, v:v), 95 °C. (g) 1-Methylpiperazine or 1-formylpiperazine,
NaBH(OAc)3, THF, room temperature.
Table 2. Further SAR Explorations
Table 3. PAMPA Permeability and Mouse PKa of 9b, 11b, and 11d
IGF-1R
IR cell
extraction ratios
mouse human
PAMPA (nm/s)
5 mg/kg iv dose
25 mg/kg po dose
cell mechanistica mechanisticb
R1 R2
IC50 (μM)
IC50 (μM)
pH 5.0 pH 7.4 Cl (mL/min/kg)
V
ss (L/kg)
Cmax(μM)
F %
9a
H
F
0.15
0.70
0.62
0.43
0.24
0.44
0.52
0.44
0.71
0.55
0.66
0.65
0.64
0.50
9b
1090
204
1100
1050
672
4
7
1.0
1.2
4.9
20.5
3.1
162
18
9b
0.017
0.026
0.008
0.025
0.014
0.076
0.26
11b
11d
11a
11b
11c
11d
H
F
CHO
CHO
CH3
CH3
145
21
1.9
27
aCompounds were dosed as freebase in female CD-1 mice.
0.048
0.32
H
F
0.068
tion of in vivo inhibition of tumor IGF-1R/IR phosphorylation
could be correlated to in vivo efficacy. In this GEO cell line, 9b
fully inhibited phosphorylation of IGF-1R and IR in vitro in a
dose-dependent manner (Figure 3a), leading to downstream
inhibition of pAKT (Figure 3b), with antiproliferative effects
correlating with IR and IGF-1R inhibition (EC50 = 130 nM).
aLISN cell line. b HepG2 cell line.
and is sensitive to dual inhibition of IGF-1R and IR.26 More-
over, the line forms tumors in vivo and is an ideal model for
tumor growth inhibition studies where the degree and dura-
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Figure 3. Inhibition of cellular signaling and proliferation by 9b. (a) Effect of varying concentrations of 9b on IGF-1R and IR
phosphorylation in human GEO tumor cells. (b) Effect of varying concentrations of 9b on pAkt in human GEO tumor cells. (c) Effect of
varying concentrations of 9b on cell proliferation for IR and IGF-1R DC tumor cell models.
Table 4. Median Pharmacokinetic Parameters for Compound 9b Following Oral Administration in Different Species
species
dose (mg/kg)
C
max (μM)
AUC (ng h/mL)
CL (mL/min/kg)c
V
ss (L/kg)c
F %
rat (F)
25a
30b
25b
11.3
10.8
35.2
62415
31383
4
15
4
0.97
0.55
1.00
64
97
rhesus monkey (M)
mouse (F)
240013
100
a Free base of 9b was dosed; vehicle, 50:50 PEG-400:25 mM tartaric acid. b HCl salt of 9b was dosed; vehicle, 40% w/v hydroxypropyl-β-cyclodextrin
(Trappsol). cA 5 mg/kg iv dose.
Furthermore, compound 9b was profiled in IGF-1R and IR
driven DC tumor cell lines27 in vitro and emulated the
observations observed in the GEO line, with antiproliferative
effects in both lines correlating with inhibition of both pIGF-
1R and pIR (Figure 3c). When taken together, these results
indicate that inhibition of IGF-1R and IR leads to inhibition of
downstream signaling of Akt, which results in the inhibition
of proliferation in IGF-1R and IR driven cell lines in vitro.
The pharmacokinetics of 9b was evaluated in multiple
species, including rat and rhesus monkey. As shown in Table 4,
9b demonstrated low clearance, good bioavailability, and
good exposure in these two species when dosed orally once a
day. In dose escalating PK studies, 9b gave dose proportional
exposure in these species (data not shown). Repeated oral
dosing in mouse, rat, and monkey did not showany evidence
of a systematic increase or decrease in exposure as com-
pared to single doses. Additionally, optimization of the salt
form and dose vehicle was carried out on 9b. The combina-
tion of the hydrochloride salt of 9b and 40% w/v of hydro-
xypropyl-β-cyclodextrin (Trappsol) as the vehicle resulted in
a solubility of approximately 60 mg/mL. A slight increase in
exposure was observed in mice when compared to the free
base form (Ta bl e 4). Thus, the HCl salt of 9b in combination
with the 40% w/v of hydroxypropyl-β-cyclodextrin (Trappsol)
as the vehicle was used in further in vivo profiling studies.
Pharmacokinetic/pharmacodynamic evaluation of 9b in
vivo in the GEO colon carcinoma xenograft model demon-
strated that a single oral dose of 10 mg/kg provided >70%
sustained inhibition of tumor IGF-1R phosphorylation up to
8 h, corresponding to plasma levels of >4 μM. Partial recovery
of pIGF-1R content (50% inhibition at 16 h) was observed
with a concomitant drop in the plasma drug levels to 0.38 μM
by 16 h (Figure 4a). Similar inhibitory effects of 9b on tumor
insulin receptor phosphorylation were observed (Figure 4a).
Twice daily administration at a dose of 10 mg/kg for 14 days
resulted in 91% tumor growth inhibition (TGI) in the GEO
model (Figure 4b). Furthermore, a once daily dose of
20 mg/kg resulted in comparable TGI of 85% (Figure 4b),
whereas 5 mg/kg bid only provided 31% TGI. The compound
was well tolerated with limited body weight loss (<10%).
In this TGI study, tumors from control and 9b treated animals
were removed after the last dose to investigate target
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Figure 4. (a) Correlation of inhibition of IGF-1R and IR phosphorylation and plasma drug concentration in GEO tumor xenografts following
oral dosing with 10 mg/kg of 9b. The plotted data are means ( SDs. Phospho-IGF-1R and pIR contents in GEO tumors are expressed as a
percentage of control pIGF-1R or pIR content from vehicle-treated animals, respectively. (b) Dose-response efficacy of 9b in GEO xenograft
models. Plotted data are mean tumor volumes expressed as a percentage of initial volume ( SE. Compound 9b was dosed on a once daily
(qd) or twice daily (bid) schedule for 14 days. (c) Inhibition of IGF-1R phosphorylation in GEO tumor xenografts following 14 days of oral
dosing with 9b. Data are means ( SEs.
Table 5. Plasma Protein Binding and Cytochrome P450 Inhibition
of 9b
inhibition in tumor tissue. Compound 9b at the efficacious
doses of 10 mg/kg bid or 20 mg/kg qd provided >70-90%
sustained inhibition of tumor IGF-1R phosphorylation for a
full 24 h post last dose (Figure 4c). At the lower, none-
fficacious dose of 5 mg/kg bid for 14 days, only 40-50%
pIGF-1R and pIR inhibition was observed (data not shown),
suggesting that near complete and sustained target inhibi-
tion may be required for maximum efficacy in this IGF-1R/IR
driven model. Blood glucose and insulin levels were also
measured after the last dose showing only transient eleva-
tion up to 8 h with return to normal levels by 24 h for the
efficacious dose levels. The antitumor activity of 9b was
extended into additional tumor models. For example, in a
human IGF-1R overexpressing NIH 3T3 xenograft model
(LISN), 9b demonstrated 100% TGI when dosed at a well-
tolerated dose of 10 mg/kg bid for 14 days (data not shown).
The kinase selectivity of 9b was determined by screening
against a panel 167 kinases using an in-house Caliper EZ
Reader mobility shift assay. Compound 9b only showed
significant activity (>50% inhibition at 1 μM concentration)
against IGF-1R and IR.28 Compound 9b did not show any signi-
ficant CYP inhibition against major CYP isoforms (Tabl e 5 ).
Preclinical safety screens of 9b against a broad range of 68
enzymes, receptors, and ion channels at 10 μM concentration
did not reveal any significant off-target activities. Thus, 9b is a
highly selective dual IGF-1R/IR inhibitor. The plasma protein
binding as measured by ultracentrifugation for 9b in multiple
species was moderate (Table 5). Compound 9b is not genotoxic
plasma protein binding
(ultracentrifugation)
CYP
isoform
%
IC50 (μM)
mouse
rat
98.5
96.6
97.3
3A4
1A2
2D6
>25.0
>25.0
>25.0
human
(Ames negative ( S9) and showed no detectable off-target
toxicological effects in a 14 day rat toxicology study, even at
doses and exposures above those predicted to be required for
efficacy.
In summary, a 5,7-disubstituted imidazo[5,1-f][1,2,4]triazine
series was conceived as an isosteric alternative to the imidazo-
[1,5-a]pyrazine dual IGF-1R/IR inhibitors. Optimization of the
interactions with K1003 compensated for the observed po-
tency loss due to the core change. Further chemical modifica-
tions improved the DMPK properties of the series leading to 9b,
a potent, selective IGF-1R/IR dual inhibitor with favorable
druglike properties. It possesses a profile comparable to that
of OSI-906, including excellent PK and tolerability in multiple
species and robust in vivo antitumor activity in several mouse
xenograft tumor models.
SUPPORTING INFORMATION AVAILABLE Synthetic pro-
cedure, analytical data for compound 9b, and procedures for in
vitro and in vivo assays. This material is available free of charge via
the Internet at http://pubs.acs.org.
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AUTHOR INFORMATION
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Siu, K.; Stolz, K.; Sun, Y.; Tavares, P.; Yao, Y.; Gibson, N. Novel
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(23) Mulvihill, M.; Cooke, A.; Rosenfeld-Franklin, M.; Buck, E.;
Foreman, K.; Landfair, D.; O'Connor, M.; Pirrit, C.; Sun, Y.;
Yao, Y.; Arnold, L.; Gibson, N.; Ji, Q. Discovery of OSI-906: A
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Greco, P. A.; Volk, B. R.; Mulvihill, M. J.; Crew, A. P. Synthetic
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(25) Altering the inhibitor structure from PQIP (PDB ID 3D94) by
deleting the attachment off the cyclobutyl moiety and modi-
fying the 5-position of the imidazopyrazine from CH to N
yields the depicted model.
(26) Ji, Q.; Mulvihill, M.; Rosenfeld-Franklin, M.; Cooke, A.; Feng,
L.; Mak, G.; O'Connor, M.; Yao, Y.; Pirritt, C.; Buck, E.;
Eyzaguirre, A.; Arnold, L.; Gibson, N.; Pachter, J. A novel,
potent, and selective insulin-like growth factor-I receptor
kinase inhibitor blocks insulin-like growth factor-I receptor
signaling in vitro and inhibits insulin-like growth factor-I
receptor dependent tumor growth in vivo. Mol. Cancer Ther.
2007, 6, 2158–2167.
(27) Lerner, L.; Liu, Q.; Yang, J.; et al. et al. Generation of in vivo
tumor models driven by Insulin-Like Growth Factor Receptor
IGF1R and their use in the development of OSI-906, a
selective IGF1R inhibitor. Abstracts A233, AACR-NCI-EORTC
International Conference: Molecular Targets and Cancer
Therapeutics, Nov 15-19, 2009, Boston, MA.
Corresponding Author: *To whom correspondence should be
addressed. Tel: 631-962-0627. Fax: 631-845-5671. E-mail: mjin@
OSIP.com (M.J.). Tel: 631-962-0787. Fax: 631-845-5671. E-mail:
mmulvihill@OSIP.com (M.J.M.).
ACKNOWLEDGMENT We gratefully acknowledge Dr. Yingjie Li
and Viorica M. Lazarescu for analytical support, Paul Maresca, Pete
Meyn, Roy Turton, and the Leads Discovery Group for conducting in
vitro ADMET studies, and Dr. Bob Zahler for consultation. We also
gratefully acknowledge Dr. Andrew P. Crew for valuable discussions
pertaining to the synthesis of the imidazo[5,1-f ][1,2,4]triazine as
well as Drs. Maryland Franklin and Qun-Sheng Ji for their over-
arching contributions to the OSI IGF-1R programs.
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